A variety of microencapsulation methods and compositions are known in the art. These compositions are primarily used in pharmaceutical formulations, for example, to mask the taste of bitter drugs, formulate prolonged dosage forms, separate incompatible materials, protect chemicals from moisture or oxidation, or modify the physical characteristics of the material for ease of handling and/or processing. Typical pharmaceutical encapsulation compositions include, e.g., gelatin, polyvinyl alcohol, ethylcellulose, cellulose acetatephthalate and styrene maleic anhydride. See Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton Pa. (1990).
Microencapsulation has also been applied in the treatment of diseases by transplant therapy. While traditional medical treatments for functional deficiencies of secretory and other biological organs have focused on replacing identified normal products of the deficient organ with natural or synthetic pharmaceutical agents, transplant therapy focuses on replacement of that function with cell or organ transplants. For example, the treatment of insulin-dependent diabetes mellitus, where the pancreatic islets of Langerhans are nonfunctional, can be carried out by replacing the normal secretion of insulin by the islets in the pancreas. Insulin may be supplied either by daily administration of synthetic or substitute animal insulin, or by transplantation of functional human or animal islets.
Attempts to transplant organ tissues into genetically dissimilar hosts without immunosuppression are generally defeated by the immune system of the host. Accordingly, attempts have been made to provide effective protective barrier coatings, e.g., by microencapsulation, to isolate the transplant tissues from the host immune system. However, these attempts generally have not proven to be medically practical due to incompatibility between the coating materials and the host system. As a result, these coated cell or tissue transplants are treated as foreign objects in the host's body and subject to immune rejection or destruction. Further, many of the encapsulation or coating processes developed previously have not yielded reproducible coatings having the desired porosity and thickness required for the transplanted tissue to have a long and effective functional life in the host.
Successful cell or tissue transplants generally require a coating which will prevent their destruction by a host's immune system, prevent fibrosis, and will be permeable to and allow a free diffusion of nutrients to the coated transplant and removal of the secretory and waste products from the coated transplant.
Viable tissue and cells have been immobilized in alginate capsules coated with polylysine. J. Pharm. Sci. 70:351-354 (1981). The use of these coated capsules in pancreatic islet transplantation to correct the diabetic state of diabetic animals has also been discussed. Science 210:908-909 (1981).
The prolonged reversal of the diabetic state of mice with xenografts of microencapsulated rat islets, using alginate-polylysine capsules has been reported. Diabetes 40:1511-1516 (1993). The development of transplants encapsulated in calcium alginate capsules reacted with polylysine is also described, for example, in U.S. Pat. Nos. 4,673,566, 4,689,293, 4,789,550, 4,806,355, and 4,789,550.
U.S. Pat. No. 4,744,933 describes encapsulating solutions containing biologically active materials in a membrane of inter-reacted alginate and polyamino acid.
U.S. Pat. No. 4,696,286 reports a method for coating transplants suitable for transplantation into genetically dissimilar individuals. The method involves coating the transplant with a surface conforming bonding bridge of a multi-functional material that binds chemically to a surface component of the transplant, which is enveloped in a semipermeable, biologically compatible layer of a polymer that binds chemically to the bonding bridge layer. A disadvantage of this method is that it relies upon specific interaction of the first polymer coating with acidic residues of proteins on the cell surface and thus may not provide complete coverage of tissues, particularly if other tissues are adhering to the tissue particles (e.g., acinar tissue on islets) and interfering with the desired bonding.
U.S. Pat. No. 5,227,298 describes a method for introducing a second alginate gel coating to cells already coated with polylysine alginate. Both the first and second coating of this method require stabilization by polylysine.
A downfall of many of the previously described encapsulation or coating compositions lies in their inability to provide a suitable immune barrier to prevent destruction of transplanted material. Further, many of the previously described encapsulation methods and compositions lack the structural integrity which would be desirable for encapsulation compositions in transplant methods as well as other applications. For example, alginate coatings described in the art are often either too thin, resulting in an insufficient barrier, too thick, resulting in a lack of permeability to nutrients and/or cell products required for continued functioning of the cells, or their thickness is not uniform, which results in a lack of predictability in the functioning of the encapsulated composition.
It would therefore be highly desirable to provide encapsulation compositions and methods for making them, which are capable of providing improved structural characteristics and immune protection. Such compositions and methods would find use, for example, in the production of individual transplants which can withstand mechanical, chemical or immune destruction within the host, and which would not provoke fibrogenic reactions impairing the transplant's function and which would additionally provide for free permeability of nutrients and secretory and waste products. The present invention meets these and other needs.